SUMMARY Traumatic brain injury (TBI) is a major public health problem in the U.S. which causes 30% of all injury related deaths and 7% long-term functional disabilities in survivors. Currently, 5.3 million Americans are living with permanent functional disabilities resulting from TBI with an estimated lifetime care cost of $4 million per person. New, effective treatments for TBI, especially for the late or recovery phase are urgently needed. Transcranial direct current stimulation (tDCS) has emerged as a promising therapeutic approach, and has recently been investigated as a clinical intervention for TBI. However, due to a lack of controlled animal studies, there are many important questions that need to be addressed to determine the utility of tDCS in TBI, and to refine the intervention to optimize long-term outcomes. These questions include the time windows for intervention and stimulus polarity for application. It is also unknown whether tDCS stimulates endogenous recovery and repair mechanisms that could in future studies be targeted to further enhance the effectiveness of tDCS in TBI survivors. The work in this proposal will address these key unanswered questions, to provide a basis for evaluation and future development of clinical interventions. Our central hypothesis is that tDCS applied in the recovery phase after TBI improves long-term neurologic recovery and is associated with increased migration of endogenous neuronal stem cells (NSC) to peri-infarct regions, and sustained increases in cerebral blood flow (CBF). A mouse controlled cortical impact model of TBI will be used, and repetitive tDCS treatment applied at one and three weeks after TBI. Specific Aim 1 will use a battery of advanced neurobehavioral tests for evaluation stimulus parameters and polarity and intervention time to the effects of tDCS on longitudinal improvement of neurological outcome. Specific Aim 2 will use a genetic labeling approach to assess the effects of tDCS on the migration tracking and long term phenotypic fate mapping of endogenous neural stem cells and their progeny. Specific Aim 3 will use optical imaging techniques to assess effects of tDCS on regional and microvascular cerebral circulation. Together, these studies will provide a valuable basis for improved understanding of the effects of tDCS in recovering brain, and for future refinement clinical applications.